Structure and function of small airways in asthma patients revisited

Small airways (<2 mm in diameter) are probably involved across almost all asthma severities and they show proportionally more structural and functional abnormalities with increasing asthma severity. The structural and functional alterations of the epithelium, extracellular matrix and airway smooth muscle in small airways of people with asthma have been described over many years using in vitro studies, animal models or imaging and modelling methods. The purpose of this review was to provide an overview of these observations and to outline several potential pathophysiological mechanisms regarding the role of small airways in asthma

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Constraints on black-hole charges with the 2017 EHT observations of M87*

InstrumentationHigh Energy Astrophysic

The variability of the black hole image in M87 at the dynamical timescale

The black hole images obtained with the Event Horizon Telescope (EHT) are expected to be variable at the dynamical timescale near their horizons. For the black hole at the center of the M87 galaxy, this timescale (5–61 days) is comparable to the 6 day extent of the 2017 EHT observations. Closure phases along baseline triangles are robust interferometric observables that are sensitive to the expected structural changes of the images but are free of station-based atmospheric and instrumental errors. We explored the day-to-day variability in closure-phase measurements on all six linearly independent nontrivial baseline triangles that can be formed from the 2017 observations. We showed that three triangles exhibit very low day-to-day variability, with a dispersion of ∼3°–5°. The only triangles that exhibit substantially higher variability (∼90°–180°) are the ones with baselines that cross the visibility amplitude minima on the u–v plane, as expected from theoretical modeling. We used two sets of general relativistic magnetohydrodynamic simulations to explore the dependence of the predicted variability on various black hole and accretion-flow parameters. We found that changing the magnetic field configuration, electron temperature model, or black hole spin has a marginal effect on the model consistency with the observed level of variability. On the other hand, the most discriminating image characteristic of models is the fractional width of the bright ring of emission. Models that best reproduce the observed small level of variability are characterized by thin ring-like images with structures dominated by gravitational lensing effects and thus least affected by turbulence in the accreting plasmas.https://iopscience.iop.org/article/10.3847/1538-4357/ac332e/pdfPublished versio